Continuous endothelial release of nitric oxide (NO) importantly contributes to the regulation of basal vascular tone by relaxing the underlying smooth muscle. NO may also inhibit the synthesis and vasoconstrictor effect of endothelin (ET); ET, in turn, may stimulate NO production through ET/B receptors on endothelial cells. To investigate the interactions between NO and ET in the forearm circulation, we assessed whether ET receptor blockade modifies the vasoconstrictor effect of the NO synthase inhibitor LNMMA. The vasomotor response to LNMMA (4 micromol/min for 15 min) was measured during either saline or nonselective blockade of ET/A and ET/B receptors by combined infusion for 60 min of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), in 12 normal volunteers (8 men) on 2 separate days at approximately 1 week apart. Drugs were infused into the brachial artery and forearm blood flow (FBF) was measured by strain-gauge plethysmography. During saline, LNMMA administration decreased FBF from 2.35+/-0.19 (mean+/-SEM) mL/min/dL to 1.72+/-0.12 mL/min/dL (P=0.002). Nonselective blockade of ET receptors did not significantly modify FBF (from 2.87+/-0.18 to 2.57+/-0.23 mL/min/dL; P=0.15). LNMMA infusion during ET antagonism only slightly changed FBF (from 2.57+/-0.23 to 2.29+/-0.17 mL/min/dL; P=0.05). Thus, the percent decrease in FBF induced by LNMMA was significantly higher prior to than during blockade of ET receptors (25+/-4% vs 7+/-5%; P<0.02). These findings indicate that NO contribution to the regulation of vascular tone is reduced during ET receptor blockade, suggesting that NO and ET physiologically interact in the regulation of forearm vascular tone.